Gamma gene promoter and enhancer structure in Seattle variant of hereditary persistence of fetal hemoglobin

A variant of hereditary persistence of fetal hemoglobin (HPFH), first described in a patient from Seattle, was studied by structural analysis of the gamma-globin genes. A family study suggested that the determinant for this form of HPFH, in which the HbF contains both G gamma- and A gamma-globin chains, segregated with the beta S gene. No deletions or other abnormalities were detected in the fetal to adult globin gene region by genomic mapping studies. All four gamma-globin genes were isolated from a cosmid library, and allelic pairs of gamma- globin genes were distinguished by linkage to either the beta S- or beta A-globin gene. Nucleotide sequence analysis of the four gamma- globin gene promoters revealed a total of three discrepancies compared with a reference sequence, but these were judged unlikely to be the underlying determinants. Sequence analysis of the enhancer region located 3′ to the A gamma-globin gene from the putative HPFH chromosome revealed three base substitutions, whereas this region was normal in the A gamma-globin gene linked to the beta A gene. These data raise the possibility that an alteration of enhancer function rather than promoter function could be the basis for this condition.